While the mapping of the human genome was being completed, two researchers named Douglas Hanahan and Robert Weinberg published an article in 2000, which offered an elegantly simple theory about how cancer cells develop and progress.1 In their original thesis, Hanahan and Weinberg proposed that there are six basic underlying genetic processes at work that make cancer (a notoriously complex cellular disease) happen. They called this paper the “Hallmarks of Cancer,” and they identified the main cellular processes that drive cancer as follows: (1) sustaining proliferative signaling; (2) evading growth suppressors; (3) resisting cell death; (4) enabling replicative immortality; (5) inducing angiogenesis; and (6) activating invasion and metastasis. Several years later, Hanahan and Weinberg added two additional hallmarks—reprogramming energy metabolism and avoiding immune destruction—and two enabling characteristics—genome instability and mutation and tumor-promoting inflammation to their model.2
Cancer’s Drive to Survive
Proliferative signaling sounds like something you might get a traffic ticket for, but what this essentially refers to is cancer’s ability to sustain its own growth so it can continue to spread. This is a fundamental aspect of cancer—uncontrolled cell growth and division. Normal cells are monitored by multiple systems and signals in the body to help keep cell growth and division under control. Cancer cells deregulate the normal signaling from these different systems and allow the cells to grow out of control. Normal cells respond to growth factors that signal the cell to grow and divide or to not grow. Growth factors bind to the surface of cells and the signal to grow is transmitted into the cell and converted to a sequence of biochemical signals, which unleash the genes that promote cell growth and division. Cancer cells highjack these normal signaling pathways to turn them on all the time. In this mode, cells are no longer under control of the normal activation (turning on) and inhibition (turning off) signals and continue growing and dividing unchecked.
Cancer Goes Stealth
At the same time cancer cells are utilizing the body’s resources to promote their own growth, they also need to avoid the systems that inhibit cell proliferation (evading growth suppressors), including tumor-suppressor genes. The body maintains an intricate balance between growth suppressors, genes that can neutralize powerful oncogenes (mutated genes in cancer cells), and factors that maintain healthy cell growth. When the function and signal from tumor-suppressor genes are lost, it means that the cells do not “hear” the message to stop growing. As a result, growth continues out of control. Now that your phone line has been severed, cancer cuts power to your alarm system as well. Your body is left in the dark while cancer progresses.
Cancer as Zombie Vampire
When he was in the advanced stages of brain cancer, David Servan-Schreiber reported growing fears as he was falling asleep that he would be attacked by vampires. He feared that nocturnal monsters immune from death were seeking to cut his own life short. While the vampires in David’s dreams were imaginary, the comparison to cancer is apt. Like vampires and zombies roaming city streets at night, cancer cells find ways to circumvent the body’s system of cell destruction, so they resist cell death and become immortal and mutate indefinitely.
Cell Suicide: One of the most effective ways our system maintains control over inappropriate cell growth and division is through what is called apoptosis—spontaneous cell death or cell suicide. Factors within the cell and signals from outside cells can trigger this death-inducing process. Once apoptosis starts to take place, the cell is progressively broken down and then consumed by its neighbors and phagocytic (“cell-eating”) cells (think Pac-Man). It is, of course, in the tumor cells’ best interest to evade apoptosis, so they can grow unregulated. They do so both through the loss of tumor-suppressor gene function and by increasing the expression of anti-apoptotic genes. By up regulating, or turning on, anti-apoptotic proteins, the cell avoids apoptosis, even though the internal and external processes are sending signals to activate cell death.
Cell Explosion: A second way abnormal cell growth is controlled is through necrosis. Unlike apoptosis, necrotic cells become bloated and explode. A consequence of having the cells explode instead of being “digested” by the system is that the cell death results in the release of certain proteins into the surrounding tissue environment. These include proteins that are pro-inflammatory in nature and recruit inflammatory cells of the immune system to come to the site of the cell explosion and remove necrotic debris. Although this may sound like a good process, first responders rushing to the scene of an accident, recent evidence suggests that immune inflammatory cells can sometimes be actively tumor-promoting because they can foster angiogenesis (the formation of new blood vessels) and cell proliferation. In fact, having excessive numbers of cells undergoing necrosis may be a cancer risk factor.
Cancer’s Bid for Eternal Life
Normal healthy cells have a limited number of growth-and-division cycles. Cancer cells, on the other hand, have processes activated enabling replicative immortality. What typically limits cell growth after successive replications and divisions is either senescence, a cell’s loss with age of its ability to divide, or cell crisis, which involves cell death (either through apoptosis or other means). If cells evade a state of senescence, then they typically enter a state of crisis and ultimately die. However, cancer cells evade both processes and take on the ability for unlimited replication. This transition is called cell immortalization.
One component within a cell that helps to ensure a cell’s integrity is the telomeres, the protective tips on the end of each pair of our twenty-three chromosomes that typically shorten as people age. Elissa Epel, a professor of psychology at the University of California, San Francisco, and coauthor of The Telomere Effect, has found that lifestyle choices are related to telomere length, which can be a predictor of disease and longevity. Every time a cell divides, the telomere length shortens. So, at a certain point, the telomere is too short for the cell to continue dividing and it becomes senescent (too old to replicate). But, in that state, the environment becomes ripe for cancer. “Once cells get old and get senescent, they become a source for inflammation, which creates a place for cancer to grow,” Epel explains. In her research, Epel has found that chronic stress leads to telomere shortening. As telomeres shorten and cells continue to replicate, this can lead to chromosomal instability and damage, a risk factor for mutations. So people who are always stressed can have “older cells” that are more vulnerable to disease at a younger age. Yet, as we will see, healthy lifestyle can slow telomere shortening and reverse the harms of stress on our telomeres.
Telomerase, an enzyme within the nucleus of cells, helps to maintain the integrity of the telomeres. Although largely found at low levels in normal cells, cancer cells and immortalized cells have abnormally high levels of telomerase, allowing the cell to continue to replicate without telomere shortening. Meanwhile, if telomerase levels are low and telomeres get short enough, a successive cell division could lead to a chromosomal aberration. At that point, if the cell does not undergo crisis or apoptosis, a tumor can start to form. Through abnormal telomerase levels and proliferation-associated abnormalities, cells can become immortalized. This allows the cells to avoid a key anticancer defense of senescence and cell death. It is cancer’s ticket to eternal life.
Let There Be Blood
Both normal tissues and tumors require a healthy blood supply to help bring in nutrients and oxygen and to remove waste products and carbon dioxide. During the early formation of an embryo and then prenatal development, the vasculature develops when new endothelial cells form together into tubes (vasculogenesis), in addition to the sprouting of new vessels (tubes) from existing vessels. This sprouting process is called angiogenesis. Once formed, the vascular system remains in place to support the body. Angiogenesis is turned on within the adult body as part of wound healing and female reproductive cycling. But this happens only for a short period of time and then stops. During tumor formation and development, an “angiogenic switch” remains on, allowing new blood vessels to be formed that help maintain the growth of the tumor. This is yet another example of how cancer tricks our normally balanced systems, permanently turning on a switch that was meant to go on and off, creating a constant state of growth, replication, or in this case—blood supply—to keep the cancer cells nourished.
Cancer’s Search for a New Home
The spread of cancer from its original site to other parts of the body is usually what makes cancer lethal—activating invasion and metastasis. Medical interventions are most successful when cancer is found early and confined to only one site in the body. Although progress has been made at controlling cancer once it has metastasized, this is the area that still poses tremendous challenges and is the primary cause of cancer-related death.
Invasion and metastasis is a multistep process. It begins with the invasion of cancer cells into nearby blood and lymph vessels. This is followed by the cancer cells moving from these transport systems into the other tissues to form microscopic nodules of cancer cells that eventually grow until they become tumors that are large enough to be seen on scans. This last step is called “colonization.”
Normally, cells are attached to their scaffolding, the extracellular matrix. If a cell detaches, it is supposed to undergo a process called anoikis—a form of programmed cell death. Tumor cells undergo a process that allows them to avoid anoikis, become migratory, and travel throughout the body. They also start to take on stem-cell characteristics, allowing them to land anywhere and adapt to the new surrounding tissues.
Once cancer cells have avoided the body’s natural process of cell death and transformed into freely circulating, adaptive cells, they are in search of a new home to “colonize.” Cancer cells are not initially adapted to the microenvironment of the tissue where they land. These cells might require hundreds of distinct colonization programs to get activated to allow the cells to grow and thrive. In this state they can also reseed and form additional colonies by further circulating in the body away from the metastatic site.
By adopting an anticancer lifestyle, you are doing everything possible to make the tumor microenvironment inhospitable to tumor growth. This makes it harder for these colonizing cancer cells to settle in and find a new home.
Cancer Siphons Your Tank
Because cancer cells replicate at a higher rate than other cells in the body, it is essential that they have the necessary “fuel” to maintain growth and cellular division—reprogramming energy metabolism. Glucose is a key source of fuel to maintain cell growth. Otto Warburg, who won the Nobel Prize in Medicine in 1931, documented a unique feature of cancer cells: even in the presence of oxygen, cancer can reprogram its energy production, by limiting energy generation largely to glycolysis, leading to a process that has been called “aerobic glycolysis.”
Energy produced mainly through glycolysis is much less efficient at producing energy for the cell. For the cancer cells to make up for this lack of efficiency in energy production, they require an increase in glucose transporters. Rapidly growing tumor cells have glycolic rates up to two hundred times higher than those of normal cells. This can occur even if oxygen is plentiful. As many tumor types seem to thrive in a microenvironment with low levels of oxygen (hypoxic conditions), efficiently transferring energy through glycolysis allows for increased levels of glucose to enter the cell. A growing tumor can be thought of as a construction site, and as today’s researchers explain it, the Warburg effect opens the gates for more trucks to deliver building materials (in the form of glucose molecules) in order to have more energy for cancer to proliferate.
Cancer Goes Undercover
A newly emerged hallmark that has received a lot of attention in the past five years is the ability of cancer cells to avoid immune destruction. We know that if components of our immune system are overactive for too long (inflammation), this state can facilitate many hallmark processes. However, the immune system also plays an important role in keeping cancer at bay. T cells are a type of white blood cells that patrol our bodies looking for cells that have been transformed into cancerous cells. The presence of T cells is a good sign for cancer patients. For example, patients with colon and ovarian cancer who have greater infiltration of certain immune cells into the tumor microenvironment have a better prognosis. On the other hand, individuals who have compromised immune systems for extensive periods of time (like people who received an organ transplant or patients with HIV/AIDS) have a higher rate of developing certain cancers. This has led to development of treatments that can boost the immune system.
But as with many of our body’s surveillance systems, cancer has found a way to neutralize this immune response. Cancer cells have the capacity to bind receptors on activated T cells and effectively turn them off. The discovery that cancer cells can essentially put the brakes on the immune system has led to a new treatment for cancer, immunotherapy, with what are called checkpoint inhibitors. These drugs help to prevent the cancers cells from turning off the immune system. Checkpoint inhibitors have changed the landscape for cancer treatment and have led to dramatic responses in some patients.
The Green Light for Cancer Growth
The multistep process of tumorigenesis (in which cancer cells survive, proliferate, and travel throughout the body), supported by one or more of the hallmark steps listed above, is made possible by two enabling characteristics. The most important is genomic instability, which leads to increased mutations that help trigger the hallmark capabilities. The second enabling characteristic is the inflammatory state of premalignant and malignant cells. This inflammatory state can help promote tumor growth and progression.
Genome Instability and Mutation: How Cancer Is Born
Mutation or another genetic aberration is a necessary first step for engaging and activating the hallmarks. Cancer is a disease of abnormal genes and gene expression. It is the alteration of the genes that sets off tumorigenesis. This can take place due to an inherited genetic phenotype, but as we know, inherited genetic abnormalities are responsible for only 5 to 10 percent of cancers. More often, gene abnormalities come about through gene mutations that you acquire during your lifetime (like from carcinogens in tobacco smoke) or through the modification of expression of nonmutated genes that are influenced by lifestyle factors.
Although spontaneous mutations that lead to cancer are always taking place in the body, genome maintenance systems are active to ensure these mutations remain at as low a rate as possible. It is the shutting down of the genome maintenance process that ultimately allows mutations to form and grow into cancers. Cancer cells themselves can also trigger increased rates of mutation and suppress the genome maintenance systems.
The DNA maintenance machinery, referred to as the “caretakers” of the genome, are a set of genes that help to maintain the integrity of the DNA to decrease persistence of mutations. Defects in these genes will allow mutations to prosper and start the tumorigenic process. If the genes responsible for DNA repair, senescence, or apoptosis are not activated at the time of mutation, then the cells will continue to proliferate unchecked and tumorigenesis begins.
Genome maintenance and repair defects are now recognized as a critical first step enabling the start of the tumorigenic process. The vast majority of tumors can be linked back to the instability of the genome as the first step in cancer development. As discussed in part 2, different lifestyle factors are linked with these enabling features. Maintaining the structural integrity of our DNA and decreasing the mutagenic process is the first step in making our body inhospitable to cancer development and growth.
Inflammation: Cancer’s Special Sauce
Inflammatory processes have long been recognized as a necessary step in tumorigenesis for most cancers. Nearly all cancer contains immune cells. The presence of some types of immune cells is a good thing, as this indicates the immune system is trying to fight the tumor. However, other immune cells can be tumor promoting by causing inflammation. With inflammation, the immune cells release molecules that can promote the hallmark capabilities, including growth factors that sustain proliferative signaling; survival factors that limit cell death; factors that facilitate and increase angiogenesis, invasion, and metastasis; and signals that allow cancer cells to travel through the body. Inflammatory cells also can release chemicals that are mutagenic (cause mutations) that help accelerate the malignant process. Inflammation has been noted at the earliest stages of tumorigenesis and can help in the transition of early malignant cells into full-blown cancer.
The Wound That Never Heals
In the above discussion of the cancer hallmarks and enabling characteristics, each area is presented somewhat in isolation from the other. However, interaction occurs between all the areas and this takes place in what is called the tumor microenvironment. The tumor microenvironment is made up of different cell types and proteins that can either foster an environment supportive of cancer growth or an environment that is hostile to cancer growth.
Within the tumor microenvironment are cancer stem cells. These cells, thought to be an originating source of the tumor, are more resistant to treatment than other cancer cells, and help to seed the cancer outside of the primary site in distant organs, leading to metastases. Within the tumor microenvironment are also endothelial cells that can form blood vessels. These cells are critical in the formation of the vascular system to help provide a new vasculature and blood supply to the growing tumor.
It is now clear that inflammation is a double-edged sword. When inflammation becomes chronic, components that were once tumor controlling become tumor promoting. For example, fibroblasts are cells that are critical in the wound-healing process, and they seem to be abundant at tumor sites. What are now termed cancer-associated fibroblasts are known to play a role in cell proliferation, angiogenesis, invasion, and metastasis.
The complex communication that is taking place between these cells in the tumor microenvironment and cells that infiltrate and circulate in the body is what allows a cancer cell to thrive and survive or to be thwarted and die. It is interesting to note that some important processes necessary for cancer to grow—inflammation, recruitment of fibroblasts, increase in angiogenesis—are the same processes that are needed for wound healing. This has led some to suggest that tumors could be viewed as wounds that never heal. What is potentially healthy for a short period of time—inflammation to heal a wound—can become harmful when it becomes a chronic condition.